The overall objective of Project 1 is to define the role of sex hormones in regulating the innate immune system of the FRT. Epithelial cells within the fallopian tube, uterus, cervix and vagina are the first line of defense against potentially pathogenic microbes and are individually responsive to estradiol and progesterone. In studies proposed in this application, we will test the hypothesis that epithelial cells represent the front line of the innate immune system throughout the human FRT and that innate immune protection by these cells is precisely regulated by female sex hormones. These studies will define the mechanisms whereby sex hormones influence phenotype, innate function, and communication between the innate and adaptive immune systems. We postulate that the innate immune responses of epithelial cells are under hormone control and that, in addition to conferring protection, these cells are capable of initiating an adaptive immune response. More specifically, we will: 1) Define the processes by which sex hormones modulate anti-bacterial activity, defensins and Secretory Leukocyte Protease Inhibitor (SLPI) produced by epithelial cells throughout the FRT; 2) Determine if exposure to specific PAMP (antigens) enhances or limits continued expression/production of anti-bacterial activity, defensins and SLPI in a way which is mediated through TLRs, and is precisely controlled by sex hormones; 3) Examine the role of sex hormones in regulating cytokine expression by reproductive tract epithelial cells in the presence and/or absence of PAMP; and 4) Define the role of sex hormone environment in modulating the interactions between reproductive tract epithelial cells and immune cells and determine if sex hormones directly influence links between the innate and adaptive immune systems. Understanding how the immune system in the reproductive tract can respond to bacterial and viral challenges requires that we understand the unique characteristics of the immune system in the female reproductive tract and the ways in which the innate and adaptive immune system are either enhanced and/or suppressed at particular times in a woman?s life. These studies should provide the basis of knowledge essential for understanding the role of hormones in autoimmune diseases such as Multiple Sclerosis, the prevention of local infection in the genital mucosa, and the management of sexually transmitted diseases as well as the treatment of gynecological cancers and endometriosis.